Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination

Abstract

Piecha G, Koleganova N, Gross M-L, Geldyyev A, Adamczak M, Ritz E. Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. Am J Physiol Renal Physiol 295: F137-F144, 2008. First published April 23, 2008 doi:10.1152/ajprenal.00065.2008.-Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle-and dihydralazine-treated groups but was significantly lowered in the SNXϩlosartan as well as in the SNXϩlosartanϩspironolactone groups and had not progressed further in the SNXϩspironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape; renin-angiotensin system GLOMERULOSCLEROSIS AND INTERSTITIAL fibrosis tend to progress over time even if the primary insult to the kidney is no longer operative (11). Blocking the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1 ) blockers slows progression in various experimental models and in patients with chronic kidney disease (11). In humans the possibility to reverse established glomerular lesions was clearly demonstrated in diabetic nephropathy after isolated pancreatic transplantation (7). In the renal ablation model in the rat, reversal of glomerulosclerosis was seen after administration of high-dose ACE inhibitors or AT 1 blockers (2,8,16). In this model, aldosterone accelerated progression of glomerulosclerosis independently of ANG II (10, 13). This finding is clinically relevant because frequently, during prolonged treatment with ACE-inhibitors or AT 1 blockers, "aldosterone breakthrou...

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